The Use of Transcranial Focused Ultrasound for the Treatment of Neurodegenerative Dementias

Parkinson Disease Clinical Trial

Official title:

The Use of Transcranial Focused Ultrasound for the Treatment of Neurodegenerative Dementias

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT04250376
• Other study ID #: 32222-1
• Status: Enrolling by invitation
• Phase: N/A
• Start date: November 27, 2017
• Est. completion date: January 2025

Study information

• Verified date: March 2023
• Source: Neurological Associates of West Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this open label study is to evaluate longer term tolerability and early efficacy of transcranial ultrasound in the treatment of patients with mild cognitive impairment or dementia.

Description:

The present study is designed as an open label study of patients with mild cognitive impairment (MCI) or dementia to evaluate longer term tolerability and early efficacy of transcranial ultrasound treatment.

Baseline and outcome measures in this study utilize validated tests that are appropriate for repeated measures which are not affected by practice effects. For patients with amnestic predominant cognitive change, the target will be the mesial temporal lobe through a trans temporal scalp window. Targeting will include reference to scalp fiducials based on the obtained MRI and Transcranial Doppler (TCD) waveform confirmation will be obtained because of the ability of TCD to record Doppler signal from the posterior cerebral artery that runs medial to the mesial temporal lobe.

On the day of the ultrasound appointment, patients will undergo ten to thirty minutes of transcranial ultrasound treatment. The sonification device will be aimed at the hippocampus or the putamen and substantia nigra, depending on the predetermined condition. Targeting will include reference to scalp fiducials based on the obtained MRI; confirmation of target accuracy will either be obtained by Doppler waveform confirmation or optical tracking technology which co-registers patient neuroimaging with real space. Patients will undergo 8 total sessions of focused ultrasound. Patients will be evaluated at baseline and upon final ultrasound treatment using the same measures obtained upon entry. Safety and any adverse events will be monitored closely.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 100
• Est. completion date: January 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years to 93 Years

Eligibility

Inclusion Criteria:

• CDR stage of at least 0.5 (mild cognitive impairment)

• At least one pathognomic imaging biomarker of a neurodegenerative process.

Exclusion Criteria:

• Cognitive decline clearly related to an acute illness

• Subjects unable to give informed consent

• Subjects with scalp rash or open wounds on the scalp (for example from treatment of squamous cell cancer)

• Advanced terminal illness

• Advanced kidney, pulmonary, cardiac or liver failure

• Subjects who would not be able to lay down without excessive movement in a calm environment sufficiently long enough to be able to achieve sleep

• Subjects with major depressive disorder

• Subjects with vascular causes of dementia

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognitive Dysfunction
• Dementia
• Mild Cognitive Impairment
• Mild Dementia
• Parkinson Disease

Intervention

Device:
• Focused Transcranial Ultrasound
The FDA has determined the power intensity limits that are safe for clinical use; the proposed equipment works within these parameters. Furthermore, monitoring sessions up to one hour as proposed in this study are routinely used in patients even with acute brain injury at 2 megaHertz without any reports of complications induced by the ultrasound device. No brain heating, cavitation or bleeding has been identified with the proposed equipment and protocol. For each individual safety can be followed by performing a selective mental status exam at each session completion (for example for hippocampal targets, there will be a delayed recall memory test).

Locations

Country	Name	City	State
United States	Neurological Associates of West LA	Santa Monica	California

Sponsors (1)

Lead Sponsor	Collaborator
Neurological Associates of West Los Angeles

Country where clinical trial is conducted

United States, 

References & Publications (44)

Bohnen NI, Albin RL, Koeppe RA, Wernette KA, Kilbourn MR, Minoshima S, Frey KA. Positron emission tomography of monoaminergic vesicular binding in aging and Parkinson disease. J Cereb Blood Flow Metab. 2006 Sep;26(9):1198-212. doi: 10.1038/sj.jcbfm.9600276. Epub 2006 Jan 18. — View Citation

Burack MA, Hartlein J, Flores HP, Taylor-Reinwald L, Perlmutter JS, Cairns NJ. In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia. Neurology. 2010 Jan 5;74(1):77-84. doi: 10.1212/WNL.0b013e3181c7da8e. — View Citation

Burgess A, Dubey S, Yeung S, Hough O, Eterman N, Aubert I, Hynynen K. Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology. 2014 Dec;273(3):736-45. doi: 10.1148/radiol.14140245. Epub 2014 Sep 15. — View Citation

Chen K, Lu Z, Xin YC, Cai Y, Chen Y, Pan SM. Alpha-2 agonists for long-term sedation during mechanical ventilation in critically ill patients. Cochrane Database Syst Rev. 2015 Jan 6;1(1):CD010269. doi: 10.1002/14651858.CD010269.pub2. — View Citation

Edison P, Rowe CC, Rinne JO, Ng S, Ahmed I, Kemppainen N, Villemagne VL, O'Keefe G, Nagren K, Chaudhury KR, Masters CL, Brooks DJ. Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J Neurol Neurosurg Psychiatry. 2008 Dec;79(12):1331-8. doi: 10.1136/jnnp.2007.127878. Epub 2008 Jul 24. — View Citation

Fitzgerald PJ. Is elevated norepinephrine an etiological factor in some cases of Alzheimer's disease? Curr Alzheimer Res. 2010 Sep;7(6):506-16. doi: 10.2174/156720510792231775. — View Citation

Fucke T, Suchanek D, Nawrot MP, Seamari Y, Heck DH, Aertsen A, Boucsein C. Stereotypical spatiotemporal activity patterns during slow-wave activity in the neocortex. J Neurophysiol. 2011 Dec;106(6):3035-44. doi: 10.1152/jn.00811.2010. Epub 2011 Aug 17. — View Citation

Gomperts SN, Rentz DM, Moran E, Becker JA, Locascio JJ, Klunk WE, Mathis CA, Elmaleh DR, Shoup T, Fischman AJ, Hyman BT, Growdon JH, Johnson KA. Imaging amyloid deposition in Lewy body diseases. Neurology. 2008 Sep 16;71(12):903-10. doi: 10.1212/01.wnl.0000326146.60732.d6. — View Citation

Hsiao IT, Weng YH, Hsieh CJ, Lin WY, Wey SP, Kung MP, Yen TC, Lu CS, Lin KJ. Correlation of Parkinson disease severity and 18F-DTBZ positron emission tomography. JAMA Neurol. 2014 Jun;71(6):758-66. doi: 10.1001/jamaneurol.2014.290. Erratum In: JAMA Neurol. 2014 Jun;71(6):803. — View Citation

Iliff JJ, Goldman SA, Nedergaard M. Implications of the discovery of brain lymphatic pathways. Lancet Neurol. 2015 Oct;14(10):977-9. doi: 10.1016/S1474-4422(15)00221-5. No abstract available. — View Citation

Ito H, Shinotoh H, Shimada H, Miyoshi M, Yanai K, Okamura N, Takano H, Takahashi H, Arakawa R, Kodaka F, Ono M, Eguchi Y, Higuchi M, Fukumura T, Suhara T. Imaging of amyloid deposition in human brain using positron emission tomography and [18F]FACT: comparison with [11C]PIB. Eur J Nucl Med Mol Imaging. 2014 Apr;41(4):745-54. doi: 10.1007/s00259-013-2620-7. — View Citation

Jagust W. Is amyloid-beta harmful to the brain? Insights from human imaging studies. Brain. 2016 Jan;139(Pt 1):23-30. doi: 10.1093/brain/awv326. Epub 2015 Nov 27. — View Citation

Jordao JF, Thevenot E, Markham-Coultes K, Scarcelli T, Weng YQ, Xhima K, O'Reilly M, Huang Y, McLaurin J, Hynynen K, Aubert I. Amyloid-beta plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound. Exp Neurol. 2013 Oct;248:16-29. doi: 10.1016/j.expneurol.2013.05.008. Epub 2013 May 21. — View Citation

Kim H, Chiu A, Lee SD, Fischer K, Yoo SS. Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters. Brain Stimul. 2014 Sep-Oct;7(5):748-56. doi: 10.1016/j.brs.2014.06.011. Epub 2014 Jul 2. — View Citation

Kotagal V, Bohnen NI, Muller ML, Frey KA, Albin RL. Cerebral Amyloid Burden and Hoehn and Yahr Stage 3 Scoring in Parkinson Disease. J Parkinsons Dis. 2017;7(1):143-147. doi: 10.3233/JPD-160985. — View Citation

Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. 2014 Dec;76(6):845-61. doi: 10.1002/ana.24271. Epub 2014 Sep 26. — View Citation

Lavialle M, Aumann G, Anlauf E, Prols F, Arpin M, Derouiche A. Structural plasticity of perisynaptic astrocyte processes involves ezrin and metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12915-9. doi: 10.1073/pnas.1100957108. Epub 2011 Jul 13. — View Citation

Lee W, Kim H, Jung Y, Song IU, Chung YA, Yoo SS. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Sci Rep. 2015 Mar 4;5:8743. doi: 10.1038/srep08743. — View Citation

Leinenga G, Gotz J. Scanning ultrasound removes amyloid-beta and restores memory in an Alzheimer's disease mouse model. Sci Transl Med. 2015 Mar 11;7(278):278ra33. doi: 10.1126/scitranslmed.aaa2512. — View Citation

Leshchyns'ka I, Liew HT, Shepherd C, Halliday GM, Stevens CH, Ke YD, Ittner LM, Sytnyk V. Abeta-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease. Nat Commun. 2015 Nov 27;6:8836. doi: 10.1038/ncomms9836. — View Citation

Lim AS, Ellison BA, Wang JL, Yu L, Schneider JA, Buchman AS, Bennett DA, Saper CB. Sleep is related to neuron numbers in the ventrolateral preoptic/intermediate nucleus in older adults with and without Alzheimer's disease. Brain. 2014 Oct;137(Pt 10):2847-61. doi: 10.1093/brain/awu222. Epub 2014 Aug 20. — View Citation

Lin GG, Scott JG. Investigations of the constitutive overexpression of CYP6D1 in the permethrin resistantLPR strain of house fly (Musca domestica). Pestic Biochem Physiol. 2011 Jun;100(2):130-134. doi: 10.1016/j.pestbp.2011.02.012. — View Citation

Mander BA, Marks SM, Vogel JW, Rao V, Lu B, Saletin JM, Ancoli-Israel S, Jagust WJ, Walker MP. beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci. 2015 Jul;18(7):1051-7. doi: 10.1038/nn.4035. Epub 2015 Jun 1. — View Citation

Nir Y, Staba RJ, Andrillon T, Vyazovskiy VV, Cirelli C, Fried I, Tononi G. Regional slow waves and spindles in human sleep. Neuron. 2011 Apr 14;70(1):153-69. doi: 10.1016/j.neuron.2011.02.043. — View Citation

O'Donnell J, Ding F, Nedergaard M. Distinct functional states of astrocytes during sleep and wakefulness: Is norepinephrine the master regulator? Curr Sleep Med Rep. 2015 Mar;1(1):1-8. doi: 10.1007/s40675-014-0004-6. Epub 2015 Jan 29. — View Citation

Petrou M, Bohnen NI, Muller ML, Koeppe RA, Albin RL, Frey KA. Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia. Neurology. 2012 Sep 11;79(11):1161-7. doi: 10.1212/WNL.0b013e3182698d4a. Epub 2012 Aug 29. — View Citation

Petrou M, Dwamena BA, Foerster BR, MacEachern MP, Bohnen NI, Muller ML, Albin RL, Frey KA. Amyloid deposition in Parkinson's disease and cognitive impairment: a systematic review. Mov Disord. 2015 Jun;30(7):928-35. doi: 10.1002/mds.26191. Epub 2015 Apr 16. — View Citation

Ricci S, Dinia L, Del Sette M, Anzola P, Mazzoli T, Cenciarelli S, Gandolfo C. Sonothrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2012 Jun 13;(6):CD008348. doi: 10.1002/14651858.CD008348.pub2. — View Citation

Scarcelli T, Jordao JF, O'Reilly MA, Ellens N, Hynynen K, Aubert I. Stimulation of hippocampal neurogenesis by transcranial focused ultrasound and microbubbles in adult mice. Brain Stimul. 2014 Mar-Apr;7(2):304-7. doi: 10.1016/j.brs.2013.12.012. Epub 2014 Jan 28. — View Citation

Schlesinger D, Benedict S, Diederich C, Gedroyc W, Klibanov A, Larner J. MR-guided focused ultrasound surgery, present and future. Med Phys. 2013 Aug;40(8):080901. doi: 10.1118/1.4811136. — View Citation

Seitz DP, Reimer CL, Siddiqui N. A review of epidemiological evidence for general anesthesia as a risk factor for Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Dec 2;47:122-7. doi: 10.1016/j.pnpbp.2012.06.022. Epub 2012 Jul 4. — View Citation

Sevigny J, Chiao P, Bussiere T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O'Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature. 2016 Sep 1;537(7618):50-6. doi: 10.1038/nature19323. — View Citation

Shah N, Frey KA, Muller ML, Petrou M, Kotagal V, Koeppe RA, Scott PJ, Albin RL, Bohnen NI. Striatal and Cortical beta-Amyloidopathy and Cognition in Parkinson's Disease. Mov Disord. 2016 Jan;31(1):111-7. doi: 10.1002/mds.26369. Epub 2015 Sep 18. — View Citation

Shteamer JW, Dedhia RC. Sedative choice in drug-induced sleep endoscopy: A neuropharmacology-based review. Laryngoscope. 2017 Jan;127(1):273-279. doi: 10.1002/lary.26132. Epub 2016 Jul 1. — View Citation

Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, Dowsett SA, Pontecorvo MJ, Dean RA, Demattos R. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2016 Feb;12(2):110-120. doi: 10.1016/j.jalz.2015.06.1893. Epub 2015 Aug 1. — View Citation

Sivanesam K, Andersen NH. Modulating the Amyloidogenesis of alpha-Synuclein. Curr Neuropharmacol. 2016;14(3):226-37. doi: 10.2174/1570159x13666151030103153. — View Citation

Stav AL, Aarsland D, Johansen KK, Hessen E, Auning E, Fladby T. Amyloid-beta and alpha-synuclein cerebrospinal fluid biomarkers and cognition in early Parkinson's disease. Parkinsonism Relat Disord. 2015 Jul;21(7):758-64. doi: 10.1016/j.parkreldis.2015.04.027. Epub 2015 May 2. — View Citation

Su X, Meng ZT, Wu XH, Cui F, Li HL, Wang DX, Zhu X, Zhu SN, Maze M, Ma D. Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: a randomised, double-blind, placebo-controlled trial. Lancet. 2016 Oct 15;388(10054):1893-1902. doi: 10.1016/S0140-6736(16)30580-3. Epub 2016 Aug 16. — View Citation

Svetoni F, Frisone P, Paronetto MP. Role of FET proteins in neurodegenerative disorders. RNA Biol. 2016 Nov;13(11):1089-1102. doi: 10.1080/15476286.2016.1211225. Epub 2016 Jul 14. — View Citation

Terrelonge M Jr, Marder KS, Weintraub D, Alcalay RN. CSF beta-Amyloid 1-42 Predicts Progression to Cognitive Impairment in Newly Diagnosed Parkinson Disease. J Mol Neurosci. 2016 Jan;58(1):88-92. doi: 10.1007/s12031-015-0647-x. Epub 2015 Sep 2. — View Citation

Thal DR, Walter J, Saido TC, Fandrich M. Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease. Acta Neuropathol. 2015 Feb;129(2):167-82. doi: 10.1007/s00401-014-1375-y. Epub 2014 Dec 23. — View Citation

Walker L, McAleese KE, Thomas AJ, Johnson M, Martin-Ruiz C, Parker C, Colloby SJ, Jellinger K, Attems J. Neuropathologically mixed Alzheimer's and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes. Acta Neuropathol. 2015 May;129(5):729-48. doi: 10.1007/s00401-015-1406-3. Epub 2015 Mar 11. — View Citation

Whittington RA, Bretteville A, Dickler MF, Planel E. Anesthesia and tau pathology. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Dec 2;47:147-55. doi: 10.1016/j.pnpbp.2013.03.004. Epub 2013 Mar 25. — View Citation

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224. — View Citation

* Note: There are 44 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Quick Dementia Rating Scale	The Quick Dementia Rating Scale (QDRS) is an interview-based tool administered by study officials to participants' caregivers used to obtain observations from a consistent source. The QDRS form consists of 10 categorical questions (5 cognitive, 5 functional), each with 5 detailed options depicting the level of impairment as either 0 (normal), 0.5 (mild/inconsistent impairment), 1 (mild/consistent impairment), 2 (moderate impairment), or 3 (severe impairment). Based on the conversion table outlined in Dr. James Galvin's research (2015), total QDRS scores were converted to Clinical Dementia Rating (CDR) scale levels ranging from 0 (normal aging), 0.5 (mild cognitive impairment), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).	Baseline
Secondary	Repeatable Battery Assessment for Neuropsychological Status (RBANS)	RBANS assesses immediate memory, visuospatial skill, language, attention, and delayed memory. Patient performance on each subscale immediate memory, language, attention, visuospatial, and delayed memory are scored relative to validated norms for same-aged peers. A change of 8+ points in the Total Scale score, 11+ points in the Immediate Memory score, 9+ points in the Language score, 4+ points on the Attention score, 14+ points is considered significant for the Visuospatial score, and 10+ points for the Delayed Memory score are considered significant.	Baseline
Secondary	Repeatable Battery Assessment for Neuropsychological Status (RBANS)	RBANS assesses immediate memory, visuospatial skill, language, attention, and delayed memory. Patient performance on each subscale immediate memory, language, attention, visuospatial, and delayed memory are scored relative to validated norms for same-aged peers. A change of 8+ points in the Total Scale score, 11+ points in the Immediate Memory score, 9+ points in the Language score, 4+ points on the Attention score, 14+ points is considered significant for the Visuospatial score, and 10+ points for the Delayed Memory score are considered significant.	After final ultrasound (8 weeks from baseline)
Secondary	Montreal Cognitive Assessment (MoCA)	The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure copy), divided visual attention, and immediate and delayed memory of unstructured information. MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal cognitive status.	Baseline
Secondary	Montreal Cognitive Assessment (MoCA)	The MoCA evaluates frontal-executive functions (e.g., verbal abstraction and mental calculation), language (e.g., confrontation naming, phonemic fluency), orientation (e.g., person, place, date, day of the week, and time), visuospatial construction (e.g., simple figure copy), divided visual attention, and immediate and delayed memory of unstructured information. MoCA scores range from 0-30 possible points; 26 or greater is considered to reflect normal cognitive status.	After final ultrasound (8 weeks from baseline)
Secondary	Quick Dementia Rating Scale (QDRS)	The Quick Dementia Rating Scale (QDRS) is an interview-based tool administered by study officials to participants' caregivers used to obtain observations from a consistent source. The QDRS form consists of 10 categorical questions (5 cognitive, 5 functional), each with 5 detailed options depicting the level of impairment as either 0 (normal), 0.5 (mild/inconsistent impairment), 1 (mild/consistent impairment), 2 (moderate impairment), or 3 (severe impairment). Based on the conversion table outlined in Dr. James Galvin's research (2015), total QDRS scores were converted to Clinical Dementia Rating (CDR) scale levels ranging from 0 (normal aging), 0.5 (mild cognitive impairment), 1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).	After final ultrasound (8 weeks from baseline)